Anatomically, the oral cavity is composed of two parts, the vestibule and the mouth cavity proper. The vestibule is limited by the reflections of the mucous membranes, also referred to as mucosa(e), from the lips and cheeks to the gums covering the upper and lower alveolar arches respectively. The mouth cavity proper is bounded laterally and ventrally by the alveolar arches with the their contained teeth; dorsally, it communicates with the pharynx. It is roofed in by the hard and soft palates, while the greater part of the floor is formed by the tongue, the remainder by the reflection of the mucosae from the sides and under surface of the tongue to the gum lining the inner aspect of the mandible. Gingiva(e), the gum, is composed of dense, fibrous tissue which is covered with vascular mucous membrane and connected to the periosteum on the edges of the alveolar processes of the mandible and maxilla. At the neck of the teeth, the fibrous tissue of the gingiva is continuous with the periosteum lining the alveoli. Except the teeth, the entire oral cavity is lines by mucosae with a squamous epithelium lining on the surface. Inflammation of the oral mucosae which may involve the buccal and labial mucosa, palate, tongue, floor of the mouth, and the gingivae, including the periodontal pockets is referred to as stomatitis.
The mucosae of the oral cavity are normally colonized by a large and diverse microbial flora. These bacteria are constantly interacting with the host and with each other in competition for survival. The number of microorganisms in 1 ml of human saliva swallowed is approximately 100 million. About 100 billion bacteria are produced in a human oral cavity in about one liter of saliva swallowed per day. There are over 200 different species of microorganisms that can be isolated from the oral cavity. But the composition of these so-called normal floras may change according to the environment and may differ from location to location in the mouth.
Certain genera, such as the Streptococcus, Actinomyces, Neisseria, and Bacteroides appear to be found in the oral cavity of all humans in high numbers. These are referred to as "indigenous flora."
Some microbes, for example, Lactobacillus species, Streptococcus mutans, Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, diphtheroids, Nocardia, fusiform bacilli and spirochetes are nearly always present, but in low numbers (less than 1%). These are referred to as "supplemental flora", but may become indigenous if the environment changes.
"Transient flora" comprise organisms "just passing through" the host. They may be present in food or drink and may be established temporarily in the mouth, but normally cannot persist in the crowded oral environment, and quickly disappear. These include Enterobacteriaceae, Staphylococcus, yeasts, Candida and other fungi.
There normal floras usually exist in symbiotic and amphibiotic patterns in the mouth, and are normally saprophytic in nature. However, they are quite capable of assuming pathogenic tendencies, thus either precipitating or aggravating disease, and are referred to as opportunistic pathogens.
An intact oral mucosa is a definite barrier to bacterial invasion. However, should this shield be broken or penetrated, bacteria or their products may enter the underlying connective tissue and grow rapidly to infectious levels. Examination of the bacterial population in the various types of oral mucosal infections has not identified a single group of microbes which can be consistently associated with the diseases. Aerobic streptococci, facultative streptococci, numerous filamentous forms (e.g, Actinomyces), diphtheroids, Gram-negative diplococci (Neisseria), fusiform bacilli, spirochetes, and bacteroides have all been described in the lesions of various oral mucosal infections with or without a concomitant observable ulceration. Any single one of these microorganisms is probably not pathogenic when introduced alone into the healthy exposed underlying tissues not covered by an intact protective mucosa. But working in combination and growing in concert, they can cause and perpetuate serious tissue damages. During the acute inflammatory stage of the bacterial infection, a large number of bacterial endotoxins and exotoxins are released from the living or dead microbes. These toxins may cause increase in vascular permeability, increase in intravascular hydrostatic pressure, outward passage or plasma fluids, release of histamine, heparin and serotonin from the tissue mast cells, which further mediate vascular engorgement and diffusibility of fluid through the endothelium. The pathological changes associated with the acute inflammation almost invariably transform the infected part of the oral mucosa in to a beefy-red painful swelling with or without grossly observable ulceration or erosion. Regardless of the etiology which has caused the initial breakdown of the barrier of the intact oral mucosa, bacterial infection in the most important of all the local factors which may delay the normal healing and repair processes of the lesion.
Suppression or elimination of the bacterial population in an infected lesion is the most logical approach of treatment. However, since the microbes in the human mouth are highly complex in variety and very high in number and since the saliva contains numerous enzymes both of host origin and of bacterial origin which may destroy any anti-infective medicines introduced, systemic routes of administering antibacterial agents for the treatment of oral mucosal infections are generally not effective. Systemic administration of antibacterial agents by parenteral injections or by ingestion of the medicaments cannot bring about an effective bacteria-inhibiting concentration of the drug to the site of infection. In the current invention, the inventor introduces a topical dry-dosage form of antibacterial agent(s) to be used as a topical medication in form of a lozenge to bring about a "supratherapeutic" concentration of antibacterial agent(s) to the lesion of infection, to sterilize the local environment periodically four times a day. Under this topical medication, the pain associated with acute inflammation of the oral mucosa subsides in about 48 hours, and minor mucosal ulcers heal completely in about 4 days. Two clinical examples, namely recurrent minor aphthous stomatitis (also known as canker sores) and acute gingivitis (also known as acute periodontal inflammation) are useful illustrations of this approach to treatment of acute mucosal infections.
Small shallow painful mucosal ulcers of the mouth, commonly referred to as aphthous stomatitis, aphthous ulcers, canker ulcers or canker sores in the medical literature, occur in about 20-25% of the general human population and are not contagious. They often appear on the unkeratinized oral mucosal surface of the soft palate, the ventral or lateral tongue, the buccal-labial mucosa, and the floor of the mouth, and usually recur at irregular intervals with single or multiple lesions. They are often covered with a grayish white exudate and surrounded by a hyperemic or erythematous margin, and are highly sensitive, especially to acid food. The size of these ulcers is rarely more than 5 mm in diameter, but can be larger, and coalescence of multiple ulcers may occur. The pain caused by these ulcers may sometimes extend over the entire face. Small canker sores usually heal spontaneously in one to three weeks, but larger ulcers may require months to resolve, often with scarring.
Three main clinical presentations are recognized, namely, minor canker sores (recurrent aphthous stomatitis), major canker sores (recurrent aphthous stomatitis) and herpetiformn ulcers. Minor canker sores account for more than 80% of the recurrent aphthous stomatitis cases. The size of the minor canker ulcers is rarely more than 5 mm in diameter and heal within 10-14 days without scarring. Major canker sores are a rare severe form of recurrent aphthous stomatitis. These lesions are round or oval, may exceed 1 cm, and may approach 3 cm in diameter. These painful ulcers of major canker sores may persist for up to 6 weeks or longer, healing slowly with scarring. Herpetiforrn ulcers are the least common variety, characterized by multiple recurrent crops of small painful ulcers of 1-3 mm in diameter and distributed throughout the oral cavity. As many as 100 ulcers may be present at a given time, and they tend to coalesce to produce large irregular ulcers.
Although aphthous ulcers were described by Hippocrates about 2,500 years ago, the etiology of these lesions is still largely unknown. While a variety of conditions are associated with aphthous ulcers, immunologic status seems to be an important factor in initiating eruptions. A pleomorphic transitional L-form of an (x-hemolytic streptococcus had been suggested to be the causative agent for recurrent aphthous stomatitis (Graykowski, et al., "Recurrent Aphthous Stomatitis", JAMA 196:637-644, 1966; Graykowski, "Periadenitis aphthae: clinical and histopathologic aspects of lesions in a patient and of lesions produced in rabbit skin", J. Amer. Dental Association, 69:118-126, 1964). However, other investigators have failed to confirm this hypothesis. Since .alpha.-hemolytic streptococcus is one of the predominant normal inhabitants in the mouth, its role as a specific causative pathogen for canker sores is difficult to establish. Electron microscopic search of the tissue sections of the canker ulcer lesion also has failed to show evidence of an L-form streptococcus. But anaerobic streptococci which are mostly a-hemolytic probably play an important role in all secondary infections in the mouth. In some patients the incidence of the occurrences of canker sores can be definitely correlated with menstrual cycles. In other cases dietary or digestive disturbances seem to be the precipitating factors. Frequently the lesions are brought on or aggravated by nuts, chocolate, and citrus products. Prolonged fever, emotional stress, local trauma, low serum iron or ferritin levels, deficiency of vitamin B,12 or folate, malabsorption in association with celiac or Crohn's disease, food hypersensitivity and drug reaction may also precipitate outbreaks of canker sores.
The first stage of an emerging canker is a vesicle in the stratum granulosum of the mucosal squamous epithelium, produced by intraepithelial edema. ("Oral Pathology", Eds. K. H. Thoma and H. M. Goldman, 5.sup.th Edition, The C. V. Mosby Co., St. Louis, 1960, page 1067). The vesicle contains serum and degenerated epithelial cells, with little inflammatory response. However, this stage is rarely noticed, as the painful symptoms of the ulcer do not occur until the vesicle breaks, presenting an area of ulceration which disrupts the normnal epithelium of the mucosa. Once an ulcer forms, the mucosa is no longer protected by an intact epithelium and the raw surface of the ulcer is exposed to microorganisms which normally inhabit the oral cavity. Examples of such microorganisms include lactobacilli, actinomyces, leptotrichiae, non-.beta.-hemolytic streptococci, enterococci, miscellaneous gram-positive cocci, Neisseriae, diphtheroid bacilli, fusiform bacilli, bacteroides, spirochetes, and yeasts. These so-called normal flora microorganisms, when existent in normally balanced proportions, do not usually produce disease in the intact oral mucosa of a healthy person. However, in a debilitated person, for example, a malnourished patient who has had a preceding illness such as measles, scarlet fever, tuberculosis, malignancy, or immunodeficiency, these microbes working in combination can cause a severe form of acute necrotizing ulcerative gingivitis, often referred to a Vincent's gingivitis. Therefore, these microorganisms are also commonly referred to as opportunistic pathogens. While pure cultures are not pathogenic, a mixture of a spirochete, a fusiform bacillus, a vibrio, and an anaerobic streptococcus of the oral flora can produce a characteristic, transmissible infection in experimental animals.
During the development of a canker ulcer, once the vesicle is broken, the opportunistic pathogens quickly destroy the remnants of the local surface barrier of the oral mucosa, causing secondary infection and a dense acute and a chronic inflammatory cell infiltration of the exposed connective tissue of the lamina propria mucosae at the crater of the ulcer. The necrotic tissue, fibrinous exudate and the inflammatory cells constitute a yellowish-white membrane often seen clinically covering the base of an ulcer. There is also marked infiltration of the small neurovascular system in the deeper layer of the lamina propria mucosae and at the periphery of the ulcer, which may account for the highly sensitive condition of the lesion and pain-inducing neuritis. The process of healing takes place only after the inflammation subsides, followed by re-epithelialization of the ulcer, with or without scarring. (Also see copending application serial number 09/026,901 for a description of the causes and effects of such ulcers. The entire contents of this copending application are incorporated herein by reference)
Since the etiology of canker ulcers is probably multifactorial, and the precipitating conditions are numerous, causative therapy is pointless. The treatment of aphthous stomatitis to date has been palliative, using various measures to lessen the pain, to control secondary infection, and to reduce inflammatory reaction after the painful ulcer is established. The types of treatments have varied over the years according to the therapeutic means available to the practitioners at the time and according to the understandings of the limitations of these types of the treatments at the time. But in general, these types of palliative treatments have met with only limited success.
For example, in the early 1950's, a recommended local treatment of infections of the oral cavity was lozenges of penicillin. The lozenges were prepared by compression of a mixture of amorphous penicillin or benzylpenicillin and dry granules of sucrose, lactose, or a mixture of the two, and suitable binding agents. (See "The Dispensatory of the Unites States of America", 25.sup.th Edition, based on the Fifteenth Revision of the Unites States Pharmacopoeia; The Tenth Edition of The National Formulary; The British Pharmacopoeia, 1953; The First Edition of the International Pharmacopoeia, Volumes I and II, edited by A. Osol and G. E. Farrar and published by J. B. Lippincott Co., Philadelphia, 1955, pages 1007-08) Each lozenge weighed about 1 gram and contained not less than 90.0% of the prescribed or stated number of Units of penicillin. If the quantity was not specified, lozenges containing about 1000 Units (an equivalent of 0.625 mg of penicillin G) were dispensed. Although these lozenges were not specified for the topical treatment of canker ulcers, they were recommended to be employed as a topical medication for the treatment of infections in the mouth and throat. The lozenges were designed to disintegrate slowly, releasing penicillin over a period of 45 to 60 minutes, after which another lozenge was inserted, with this process continuing for 24 hours, except during meals.
However, this topical treatment of aphthous ulcers with penicillin lozenges proved ineffective and was abandoned. Furthermore, as recently as 1980, the use of penicillin for topical applications to mucous membranes and skin was not advised, as such applications were described as ineffective and likely to produce hypersensitivity. (See "The Pharmacological Basis of Therapeutics", Eds. Gilman Goodman, and Gilman, p.1136.) As a result, this type of treatment for aphthous stomatitis was not included in later teachings and in the later editions of pharmacopoeia.
In the most recent medical texts, recommended types of treatment for canker sores include a potent glucocorticoid ointment mixed with an equal volume of Orabase.TM. (active ingredient: mineral oil; available from Bristol-Myers Squibb of Canada), analgesics, topical anesthetics (such as viscous lidocaine hydrochloride), various hygienic antiseptic mouth rinses, and a topical tetracycline mouthwash four times a day for seven days. (See "Gastrointestinal Disease, Pathophysiology/Diagnosis/Management", 5.sup.th Edition, ed. by M. H. Sleisenger and J. S. Fordtran, published by W. B. Saunders Co., Philadelphia, 1993, page 273; and "The Nelson Textbook of Pediatrics", 15.sup.th Edition, ed. R. E. Berhman, R. M. Kliegman and A. M. Arvin, published by W. B. Saunders Co., Philadelphia, 1996, page 1889). However, potent glucocorticoid ointments and systemic therapy with corticosteroids are known to suppress the local and systemic immunity of the body, paving the way to other complications, such as even more severe systemic bacterial or fungal infections. Large doses of corticosteroids impair the healing response in experimental animals. Such steroids have been reported to have adverse effects on epithelial regeneration, the proliferation of fibroblasts, and the synthesis of the extracellular matrix. ("Oxford Textbook of Pathology", Vol. 1, ed. J. McGee et al., Oxford University Press, 1992, page 374) The end result of using steroids to treat an infected wound is likely to delay wound healing.
Therefore, these recommended types of treatment for canker ulcers are not commonly prescribed by the practitioners although steroids may suppress the inflammatory response and reduce the degree of ulcer pain symptomatically. More recently, a paste containing 5% of amlexanox has been approved for the topical treatment of canker sores (marketed under the name Aphthasol.TM.), which is listed in the 1998 edition of the Physician's Desk Reference. According to the data published in the Physician's Desk Reference, topical application of the Aphthasol Oral Paste to the canker sore on the average accelerates complete healing of the canker ulcer and complete ulcer pain relief by 0.7 days. Such a treatment is interpreted as "minimally effective".
Thalidomide therapy for oral aphthous ulcers is effective in some HIV-infected patients, though the adverse effects of this teratogenic drug limit its usefulness in general. Topical treatment with tetracycline suspensions or nystatin suspensions, as well as systemic therapy with penicillin, are commonly employed. A drawback to oral antimicrobial rinses and suspensions is their inability to present high enough (supratherapeutic) concentrations of the active drugs in the immediate vicinity of the ulcers to suppress the growth of the pathogens which have contributed to and continue to perpetuate the infection. For example, one protocol requires patients to hold 250 mg of tetracycline in 5-10 mg/ml suspension in the mouth for 2 to 5 minutes to coat the ulcers, then suggests swallowing the remaining liquid. This treatment is often impractical, especially for use in children. Tetracycline oral suspensions are available commercially in concentrations from about 5 mg/ml to about 10 mg/ml. Supratherapeutic concentrations of, for example, 500 mg/ml are not achievable with these solutions. Likewise, topical combination treatments utilizing pastes of crushed tetracycline tablets (150 mg in 1 ml of saline) and tissue adhesive agents, such as cyanoacrylate, cannot achieve such high levels of antibiotic. Besides, this type of treatment must be performed by a dentist.
Acute gingivitis, or acute periodontal inflammation, also has a complex etiology, including local environmental factors and systemic disturbances. The most important initial factor in causing periodontal diseases is the bacterial plaque which is a soft, sticky, mucilaginous form that accumulates on the teeth, particularly on their cervical portions. It contains adherent mucin, foodstuffs, cellular debris, and a variety of microorganisms, both living and dead. Plaque may calcify to form calculus, and newly forming plaque, overlying the calculus, in turn undergoes mineralization. The process is thus repetitive. The bacteria observed in a plaque are those of oral floras, including aerobic and anaerobic streptococci, staphylococci, lactobacilli, Actinomyces, Nocardia, bacteroides, fusiform bacilli and spirochetes. The bacterial plaque tends to progress and eventually destroys the normal anatomical relationship at the junction between the gingival mucosa and the teeth, leading to the formation of periodontal pocket. Once formed, the periodontal pocket in turn alters the local environment, becoming a locus for debris, calculus, bacteria and food. Effect becomes cause.
Under a variety of conditions, such as when there is inadequate oral hygiene or when there is a minor trauma causing breakdown of the intact protective squamous epithelium of the gum, the opportunistic bacteria may gain access into the connective tissue, to initiate a painfuil acute periodontal infection, acute gingivitis. The standard treatment has been to administer systemic antibacterial agents via parenteral injections or oral ingestion for gastrointestinal absorption with slow response, usually taking about seven to ten days to gain complete relief of pain.
An obstacle to inhibiting microbial proliferation is the fact that many bacteria arc resistant to the concentrations of antibiotics attainable in blood or in tissues during medication. This property of drug resistance may be natural or acquired. However, the growth of many "resistant" microorganisms can be inhibited in vitro by increasing the concentrations of the antibiotic to a supratherapeutic level that is not safely attainable in blood or in tissue fluids via conventional gastrointestinal absorption or intramuscular and intravenous injections. For example, Gram-negative bacilli are generally regarded as being resistant to penicillin G, even at the concentration of 16 mcg/ml which is accepted as the average peak blood level after an intravenous injection of 500 mg of penicillin G. However, if a high concentration of penicillin G is used (such as, for instance, 740 mcg/ml) as the cut-off minimum inhibition concentration (MIC) for classifying sensitive and resistant strains, many Gram-negative bacilli (including, for instance, Salmonella, Shigella, most Escherichia coli strains, all Proteus mirabilis strains and most Bacteroides strains) would fall into the "sensitive" category. Needless to say, in clinical practice, drug toxicity and rapid renal clearance usually prevent this substantial level of antibiotic being achieved in human blood and tissue fluids via systemic oral or parenteral medication.